We are using a transgenic mouse model with a known ans-specific inborn genetic impairment of the type II glucocorticoid receptor function to study the impact of the resulting deficient glucocorticoid negative feedback on the response to stress and anxiogenic stimuli, and on sensitization to stress at both the neurochemical and behavioral levels. We are also studying the modulation of target mRNA levels, particularly of the glucocorticoid 5-HT2A and 5-HT1A receptors, CRF receptor, CRF, and NPY by various pharmacological treatments in conjunction with their impact on the behavior of these transgenic mice. We have found that these animals have a greater response to amphetamine than controls and their baseline level of locomotor activity is higher than in controls during the light phase of the circadian cycle and that they have a strikingly higher startle response to acoustic stimuli and this exaggerated response is normalized by treatment with the antidepressant desipramine. This normalization of the startle response is dependent on the normalization of the glucocorticoid receptor levels rather the level of the circulating hormone itself. We know that a similar treatment normalizes the glucocorticoid receptor mRNA levels in this transgenic model. Recent preliminary data indicate that these animals bear a reduced level of 5-HT2A receptor mRNA in the frontal cortex and that this abnormality is also corrected by antidepressant treatment. We have shown that these animals become sensitized to acoustic startle while controls do not. We believe that this phenomenon might be related to a decreased level of NPY observed in the arcuate nucleus of the hypothalamus of these animals. Moreover, we have demonstrated that the desipramine treatment increases the levels of NPY in the amygdaloid complex where it is known to have an anxiolytic effect via its action in the central nucleus in particular. We plan to investigate this phenomenon further with pharmacological experiments with blood-brain barrier permeable agonists and antagonists of the NPY receptors. Moreover, we have begun pilot experiments aimed at establishing the correct parameters for fear-potentiated startle with mice. This strategy will allow us a direct behavioral assessment of the function of the central nucleus of the amygdala, which we can then correlate with neurochemical and pharmacological changes and manipulations. These studies should lead to a better understanding of the etiopathogeny of recurrent affective (unipolar and bipolar) and anxiety disorders.